Lviv National Medical University

Department of pathological physiology

PhD. Kolishetska M.A.

Neoplasia (Latin, new growth) is an abnormality of
cellular differentiation, maturation, and control of
growth.
 Neoplasms are commonly recognized by the
formation of masses of abnormal tissue (tumors)
 Neoplasia is new, uncontrolled growth of cells that is
not under physiologic control.
Nomenclature of Neoplasia

 Malignant neoplasms arising from tissue

embryologically derived from ectoderm or endoderm
are usually carcinomas. Examples include:
 Squamous cell carcinoma of cervix
 Adenocarcinoma of stomach
 Hepatocellular carcinoma
 Renal cell carcinoma
 Malignancies arising from mesoderm (connective
tissues) are usually sarcomas. Examples include:
 Leiomyosarcoma
 Chondrosarcoma
 Osteosarcoma
 Liposarcoma
 Neoplasms with more than one cell type but
arising from only one germ layer are called "mixed
tumors". The best example is the benign mixed
tumor (also called pleomorphic adenoma) of
salivary gland.
 Neoplasms with more than one cell type and
arising from more than one germ layer are called
teratomas. Such neoplasms are common in the
ovary.
 Neoplasms ending in "-blastoma" resemble primitive
embryonic tissues, which are often pediatric
neoplasms. Examples include:
 Retinoblastoma
 Neuroblastoma
 Hepatoblastoma
 Medulloblastoma
 Not all malignant neoplasms have benign
counterparts:
 Hematopoietic and lymphoid cells (as in bone marrow
and lymph node) give rise to leukemias and lymphomas.
They have no benign counterpart.
 Gliomas (astrocytomas, oligodengrogliomas,
glioblastoma multiforme, etc) arise from glial cells in the
CNS. They have no benign counterpart.
 Chemical carcinogens
 1. Polycyclic aromatic hydrocarbons
3,4-benzopyrine
1,2,5,6-dibenzoantracene
9,10-dimethyl-1,2- benzoantracene
20- methylcholantren
 2. Aromatic аmines and amides
monoаzоbenzol
2-аminofluoren
2-naphtylamine
chlornaphthisine
benzidine
 3.Nitrosamines and nitrosamides
 N,N-dimethylnitrosamine
N-nitrosopyrolidine
N-nitrosomethylаniline
N-nitrosomorpholine
N-methyl- N-nitrosourine
Tumor etiology
 3,4-benzopyrene

 Carcinogenes of this group, are usually of antropogenous origin. They
are in tobacco smoke, car-petroleum gases, blast-furnaces smoke,
chemical productions wastes, overfried food. They cause cancer or
sarcoma by their injection way. Polycyclic aromatic hydrocarbons exude
from organism by kidneys, skin, mammal glands, therefore are followed
with the neoplasms of these organs.
 Aromatic amines and amides are mainly dyestuffs. They include
monoazobenzene, benzidine, chlornaphthisine and others. These
substances are usually used for natural or synthetic fabrics colouring,
polygraphy, cosmetics production, colour-photography processes,
medications or eather insecticides synthesis that is followed with
neoplastic growth attached to skin or gastrointestinal contacts. Tumors
are usually located in liver, urinary cyst, bowels, kidneys.
Tumor etiology
The third carcinogenes group (nitrosamines and nitrosamides) cause
neoplastic processes in 40 animals species. Their carcinogenous effects upon
the humans are not proved, however the experimental data are of the great
attention. A man contacts to nitrosamines at productions. Besides, they form in
digestive canal of nitrites, nitrates and other junctions of nitrogen.

Almost all of carcinogenic matters are not active. But they acquire
carcinogenic properties due to their entering the organism. The final
cancerogenes get formed with them. Nominally these matters are followed with
neoplastic growth. It is proved, that carcinogenes react with purine bases of
DNA obligatorily. The most frequent target – is guanine, which gets methylated
or eather alkylated by cancerogenes (that means its combining to the methyl or
eather alkyl group). Changed guanine is unable to bind with cytosine, but gets
associated with thymine. The sequence of bases in DNA molecule gets
disturbed. Genes mutation arises.
 Physical agents

 Some substances cause cancer primarily through their

physical, rather than chemical, effects on cells.
 A prominent example of this is prolonged exposure
to asbestos, naturally occurring mineral fibers which are a
major cause of mesothelioma, a type of lung cancer. Other
substances in this category include both naturally
occurring and synthetic asbestos-like fibers, such
as wollastonite, attapulgite, glass wool, and rock wool, are
believed to have similar effects.
Physical agents
 Nonfibrous particulate materials that cause cancer
include powdered metallic cobalt and nickel,
and crystalline silica (quartz, cristobalite,
and tridymite).
 Usually, physical carcinogens must get inside the
body (such as through inhaling tiny pieces) and
require years of exposure to develop cancer.
Tumor etiology
 Physical carcinogenesis. To physical cancerogenes belong ionizing
and ultraviolet rays.
 The ionizing rays cause diverse genetical and chromosomal
mutations. They are followed with neoplastic growth in all of organs
almost. Skin, bones, lungs, thyroid, mammal gland neoplasms arise
in case of external irradiation. In case of ionizing radionuclides
entering inside, the tumor arises at their accumulation locations. For
example barium, calcium, strontium radionuclides cause the bone
neoplasms. Caesium, thorium radionuclides, able to cause liver, bone
marrow, stomach, thick bowel tumors.
 The ultraviolet rays render weak carcinogenic action, but they
damage the mechanisms of DNA reparation. In particular,
dimerization of thymine takes place under their dominance. As a
result an usual bases sequence in DNA molecule gets disturbed.
 Radiation

 Sources of ionizing radiation, include medical

imaging, and radon gas. Radiation can cause
cancer in most parts of the body, in all animals,
and at any age, although radiation-induced solid
tumors usually take 10–15 years, and up to 40 years,
to become clinically manifest, and radiation-
induced leukemias typically require 2–10 years to
appear.
Tumor etiology
 Viral carcinogenesis. It is proved, that tumors can be caused
by viruses. Here are some neoplasms examples of viral origin:
Rauss sarcoma in chicken, Shope papilloma in rabbits,
mammal gland cancer in rats, which arises in case of Bittner
milk factor. Viruses, which cause neoplastic growth, are called
oncogenous. They belong to the group of retroviruses. Not
many human tumors, which get caused by viruses are known.
They are Burkitt’s lymphoma (Central Africa), nasopharyngeal
cancer (China), cervix cancer. Conception of oncogen A special
theory was formulated by the end of last century,due to the
foundation of contemporary knowledge, which united all of
known carcinogenesis forms (chemical, physical, biological)
into a single universal mechanism. It had been called as
conception of oncogen.
Infection

 Worldwide approximately 18% of cancers are related

to infectious diseases.
 This proportion varies in different regions of the
world from a high of 25% in Africa to less than 10% in
the developed world.
 Viruses are usual infectious agents that cause cancer
but bacteria and parasites may also have an effect.
Infection

 A virus that can cause cancer is called

an oncovirus. These include human
papillomavirus (cervical carcinoma), Epstein-Barr
virus (B-cell lymphoproliferative
disease and nasopharyngeal carcinoma), Kaposi's
sarcoma herpesvirus (Kaposi's Sarcoma and
primary effusion lymphomas), hepatitis
B and hepatitis C viruses (hepatocellular
carcinoma), and Human T-cell leukemia virus-
1 (T-cell leukemias).
Infection
 Bacterial infection may also increase the risk of
cancer, as seen in Helicobacter pylori-
induced gastric carcinoma.
 Parasitic infections strongly associated with
cancer include Schistosoma
haematobium (squamous cell carcinoma of the
bladder) and the liver flukes, Opisthorchis
viverrini and Clonorchis sinensis
(cholangiocarcinoma).
 Common environmental factors that contribute to
cancer death include: tobacco (25-30%), diet
and obesity (30-35%), infections (15-
20%), radiation (both ionizing and non ionizing,
up to 10%), stress, lack of physical activity,
and environmental pollutants.
 Chemicals

 Many mutagens are also carcinogens, but some

carcinogens are not mutagens.
 Alcohol
 Decades of research has demonstrated the link
between tobacco use and cancer in
the lung, larynx, head, neck, stomach, bladder,
kidney,esophagus and pancreas. Tobacco smoke
contains over fifty known carcinogens,
including nitrosamines and polycyclic aromatic
hydrocarbons.
Chemicals
Cancer related to one's occupation is believed
to represent between 2-20% of all
cases. Millions of workers run the risk of
developing cancers such as lung
cancer and mesothelioma from
inhaling asbestos fibers and tobacco smoke,
or leukemia from exposure to benzene at their
workplaces
cases
 Diet and exercise
 Diet, physical inactivity, and obesity are related to
approximately 30-35% of cancer cases.
 Physical inactivity is believed to contribute to cancer
risk not only through its effect on body weight but also
through negative effects on immune
system and endocrine system.
cases
 Diets that are low in vegetables, fruits and whole grains,
and high in processed or red meats are linked with a
number of cancers.

 A high salt diet is linked to gastric cancer, aflatoxin B1, a

frequent food contaminate, with liver cancer, and Betel
nut chewing with oral cancer. This may partly explain
differences in cancer incidence in different countries for
example gastric cancer is more common in Japan with its
high salt diet and colon cancer is more common in the
United States.

 Heredity

 Less than 0.3% of the population are carriers of a genetic mutation

which has a large effect on cancer risk. They cause less than 3-10% of all
cancer. Some of these syndromes include:
 certain inherited mutations in the genes BRCA1 and BRCA2 with a
more than 75% risk of breast cancer and ovarian cancer
 tumors of various endocrine organs in multiple endocrine
neoplasia (MEN types 1, 2a, 2b)
 Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast
cancer, soft tissue sarcoma, brain tumors) due to mutations of p53
 Turcot syndrome (brain tumors and colonic polyposis)
 Familial adenomatous polyposis an inherited mutation of
the APC gene that leads to early onset of colon carcinoma.
Heredity

 Retinoblastoma, when occurring in young

children, is due to a hereditary mutation in
the retinoblastoma gene.
 Down syndrome patients, who have an
extra chromosome 21, are known to develop
malignancies such as leukemia and testicular
cancer, though the reasons for this difference
are not well understood
 Hormones

 Some hormones cause cancer, primarily by

encouraging cell proliferation.
 Hormones are an important cause of sex-related
cancers such as cancer of the breast, endometrium,
prostate, ovary, and testis, and also of thyroid
cancer and bone cancer.
Hormones

 For example, the daughters of women who have breast

cancer have significantly higher levels
of estrogen and progesterone than the daughters of women
without breast cancer. These higher hormone levels may
explain why these women have higher risk of breast cancer,
even in the absence of a breast-cancer gene.
 Similarly, men of African ancestry have significantly higher
levels of testosterone than men of European ancestry, and
have a correspondingly much higher level of prostate
cancer.
The incidence of cancer varies with:
 Age: the frequency of cancer increases with age. Most
cancer mortality occurs between ages 55 and 75; the
rate declines, along with the population base, after age
 Sex
 Prostate cancer in men and uterine cancer and breast
cancer in women are obviously sex-specific.
The incidence of cancer varies with:
 Сancer of the oropharynx, esophagus, and stomach is
more than twice as common in men, but cancers of the
gallbladder and thyroid and malignant melanoma are
more frequent in women.
Occupational, Social, and Geographic
Factors
 Occupational factors have been mentioned with
reference to an increased risk of bladder cancer in
workers in the dye industry and lung cancer in certain
miners.
Occupational, Social, and Geographic
Factors
 Epidemiologic studies also show that a patient's sexual
and childbearing histories are important.
 Women who have borne several children and have
breast-fed them have a significantly lower incidence of
breast cancer than women who elect not to breast-feed
or who are nulliparous.
Genetic backgrounds
 Inherited cancer syndromes include several well-
defined cancers in which inheritance of a single
mutant gene greatly increases the risk of developing a
tumor.
 The predisposition to these tumors shows an
autosomal dominant pattern of inheritance.
 Formation of carcinogenes
l Precarcinogene
l ↓
Proximal
carcinogene
↓
Final carcinogene
Stages of carcinogenesis
 Transformation − expression of
cell oncogene
 Promotion − division cells
 Progression− development of
tumor in a way of malignisation
Stages of carcinogenesis
 Transformation. The first stage
(transformational stage) is followed with the
cell oncogene activation. The cell acquires
unusual property, which is called
immortalisation. This is a potential
unlimited division, immortality ability.
However, the presence of active oncogene is
a readiness to division only. A cell with
active oncogene can resist in latent
(condition) for years. It does not display
itself with anything.
Stages of carcinogenesis
 Promotion. Supplementary influences
upon immortalisated cell, are necessary
to exit it out of the latent state, for
giving a push to irrepressible division.
These are provoking factors, which are
supplementary doses of chemical
cancerogenes or x-rays, retroviral
superinfection. They are named
promotors.
Stages of carcinogenesis
 Progression is the very last and the most protracted stage of
neoplastic growth development. The clearest determination of this
notion Fulds has given: “Progression is a neoplasm development in a
way of constant, irreversible, qualitative changes of its one or a few
signs". Progression is not just quantitative tumor growth, but native
change of its biological properties. One of the major Fuld’s
principles is an independent progression of separate neoplastic signs.
Its essence is the following: each tumor sign (morphological
anaplasia degree, hormones dependence degree, invasive growth
capacity, metastasing ability) evolutionizes irrespectively to the other
signs, however to the malignisation side always.
 Neoplastic growth progression reflects tumor admiring to autonomy.
It holds a neoplastic cell much more further from maternal. The main
progression index is organs and tissues structure loss by the tumor
with simultaneous cell differentiation lowering.
 Types

 A neoplasm can be benign, potentially malignant (pre-

cancer), or malignant (cancer).
 Benign neoplasms include uterine
fibroids and melanocytic nevi (skin moles). They do not
transform into cancer.
 Potentially malignant neoplasms include carcinoma in situ.
They do not invade and destroy but, given enough time,
will transform into a cancer.
 Malignant neoplasms are commonly called cancer. They
invade and destroy the surrounding tissue, may
form metastases and eventually kill the host.
 Benign tumor

 A benign neoplasm looks a lot like the tissue with

normal cells from which it originated, and has a slow
growth rate.
 Benign neoplasms do not invade surrounding tissues
and they do not metastasize. Thus, characteristics
include:
Benign tumor
 Slow growth
 Resemblance to tissue of origin (well
differentiated)
 Lack of invasion
 Absence of metastases
Signs and symptoms

 Benign tumors are very diverse, and may be asymptomatic

or may cause specific symptoms depending on their
anatomic location and tissue type. Symptoms or
pathological effects of some benign tumors may include:
 Bleeding or occult blood loss causing anemia
 Pressure causing pain or dysfunction
 Cosmetic changes
 'Hormonal syndromes' resulting from hormones secreted
by the tumor
 Obstruction, e.g., of the intestines
 Compression of blood vessels or vital organs
Benign tumor
leiomyomas
Multiple adenomatous polyps
hepatic adenoma
 Treatment

 Many benign tumors do not need to be treated at

all.
 If a benign tumor is causing symptoms, presents a
health risk, or causes a cosmetic concern for the
patient, surgery is usually the most effective
approach.
 Most benign tumors do not respond
to chemotherapy or radiation therapy, although
there are exceptions
 Cancer
 Cancer /ˈkænsər/ ( listen) (medical
term: malignant neoplasm) is a class
of diseases in which a group of cells display
uncontrolled growth, invasion that intrudes
upon and destroys adjacent tissues, and
sometimes metastasis, or spreading to other
locations in the body via lymph or blood.
Pathophysiological
characteristic of tumor
 More rapid increase in size (Unlimited of
growth)
 Unregulation of growth
 Less differentiation (or lack of
differentiation, called anaplasia)
 Tendency to invade surrounding tissues
 Ability to metastasize to distant tissues
Сharacteristics of malignant neoplasms
Tumor cells have typical caracteristic – growth autonomy.
Cultural growth is controlled at two levels – organism and tissue
ones. At organism level such control is realized with nervous and
endocrine systems, at tissues level – with biologically active
substances which are mitogenes and keylones. Neoplastic cells
display independence, growth autonomy. Its stop reacting upon
nervous, endocrine and local regulative stimuls.
Autonomy of tumor cells develops gradually. At first tumorcell
gets partially hormonal regulated (hormone dependent tumor).
Later it is perfectly irresponsible for hormones (hormone
independent tumor).
Сharacteristics of malignant neoplasms
The third characteristic feature of tumor cells – is
anaplasia, which is cells structural and biochemical
organization simplification, coming back to embryonic state.
Neoplastic cells lose a capacity for differentiation and can
not form the specific tissue complexes.
Tumor arises from one mutational maternal cell.
However such cells differ from their general ancestor by
much parameters. These distinctions consearn the cell
structure, its organelles, metabolism, specific properties
and functions. Therefore the following kinds of anaplasia are
distinguished: morphological, biochemical, physical and
chemical, functional, immunological.
Kinds of cellular аnаplasia
1. Моrphological
2. Biochemical
3. Physic-chemical
4. Functional
5. Immunological
Anaplasia

The essence of morphological anaplasia is in

appearance of atypic cultural and tissue. Description of
cultural atypic – lays in cellular polymorphism, nuclear size
increase, polynuclear state, nuclear hyperchromatosis,
nucleoluses amount increase, mitochondrias changes –
quantative size decrease, crests disappearance.

Tissue atypism – is sizes and shapes of tissue

structures change, sometimes is the total loss of
morphological tissue signs.
 Morphological anaplasia
 Polymorphism of cells
 Increase of relation nucleus
/cytoplasma
 Multinucleonic
 Hyperchromatosis of nucleuses
 Increase of quantity nucleoles
 Changes of cell оrganels
 Changes of mitochondrias
 Decrease of amount
 Decrease of sizes
 Refinition of mitochondriale
membranes
 Decrease of amount crest
 Refinition of crest
Anaplasia

Biochemical anaplasia – is the tumor cells metabolism

peculiarities. Its are aroso their genetic system changes,
enzymic spectrum of such cells gets changed. All cells get
alike by enzymic admission (unification of isoenzymic
spectrum).
The most typical biochemical feature of neoplastic cells
concern proteins and carbohydrates metabolism.
Anaplasia
Proteins metabolism peculiarities are: synthesis
activation of nucleinic acids, DNA-polymerase inactivation,
increase of proteins synthesis and decrease of proteins
disintegration.
Carbohydrates metabolism and energetic of tumor cells is
also differ of norm. The main energy sources in normal cells
are anaerobic and aerobic carbohydrates disintegration,
that is glycolysis and Krebs cycle. Neoplastic cell also
receives the energy owing to glycolysis and Krebs cycle.
However glycolysis role in tumor cell is more, than in
normal one.
The tumor cells energetic supply include: anaerobic
glycolysis activation, aerobic glycolysis presence,
oppression of Krebs cycle by powerful glycolytical enzymes
system.
 Biochemical аnaplasia
Features of protein metabolism
 1. Dysfermentosis
 2. Unification of isoenzymic spectr
 3. Activation of nucleonic acids synthesis
 4. Activation DNA-polymerase
 5. Increase of protein synthesis
 6. Decrease of protein catabolism
 Biochemical аnaplasia
Energy supply
 1. Activation of anaerobic glycolysis
 2. Present of aerobic glycolysis
 3. Activation of glycolic enzymes
- pyruvatkinase
- hexokinase
- fruitkinase
4. Inhibition of Krebs cycle
Anaplasia
Physical and chemical peculiarities of neoplastic cells:
acidosis owing to lactic acid accumulation, intracellular
hydration, raised electroconductivity, colloid viscosity
decrease, membranes surface-tension decrease, negative
membranes charge increase.
Functional anaplasia displays in loss or perversion of
tumor cells function. For example, in neoplastic thyroid cells
a surplus amount of hormones thyroxine and
triiodothyronine can be synthesized, thyrotoxicosis arises.
In other cases separate functions of tumor cells fall out, for
example, bilirubin does not get conjugated in hepatome. In
very malignant neoplastic cells functions are totally lost.
Sometimes such cells begin doing the functions, which are
not specific for them (bronchus cancer synthesizes the
gastrointestinal hormones).
 Physic-Chemical аnaplasia

 Acidosis
 Intracellular hydration
 Accumulation of potassium
 Increase of electroconductivity
 Decrease of colloid viscosity
 Increase of membranes charge
 Decrease of surfase tension
Anaplasia
Immunological anaplasia – is change of tumor cell
antigen properties. In such cells antigen admission is
changed. Several deviation kinds of antigen out of norm
admission are distinguished – antigen simplification,
antigen divergence and antigen reversion. Antigen
simplification – is the general number of neoplastic cells
antigens diminution.The idea of antigen divergence is in the
fact of neoplastic cells starting to synthesize heterologous
antigens. For example, hepatoma (liver tumor) begins
synthesizing organospecific spleenic antigens, or other
organs antigens.
Antigen reversion means neoplastic embryonic
antigens synthesis. For example, human liver cancer
synthesizes a special embryonic protein, which is -
fetoprotein.
 Immunological аnaplasia
 Antigen admission
 Antigen divergence
 Antigen reversion
Metastasis
 Metastasis is the establishment of a second neoplastic
mass through transfer of neoplastic cells from the first
neoplasm to a secondary location separate from the
original tumor.
 Metastasis occurs only in malignant neoplasms and
explains why they are life-threatening and difficult to
eradicate
Spread of Malignant Neoplasms

 By direct extension (invasion) into surrounding

tissues.
 Through lymph channels to lymph nodes
(lymphatic spread)--typical of carcinomas.
 Via the bloodstream (hematogenous spread)--
typical of carcinomas or sarcomas.
 Within body cavities (seeding)--typical of
neoplasms impinging upon body cavities, such as
the peritoneal cavity.
lung cancer
renal cell carcinoma
malignant melanoma
 Signs and symptoms

 Cancer symptoms can be divided into three groups:

 Local symptoms: are restricted to the site of the
primary cancer. They can include lumps or swelling
(tumor), hemorrhage (bleeding from the skin, mouth or
anus), ulceration and pain. Although local pain commonly
occurs in advanced cancer, the initial swelling is often
painless.
 Metastatic symptoms: are due to the spread of
cancer to other locations in the body. They can include
enlarged lymph nodes (which can be felt or sometimes
seen under the skin), hepatomegaly (enlarged liver)
or splenomegaly (enlarged spleen) which can be felt in
the abdomen, pain or fracture of affected bones,
and neurological symptoms.
Signs and symptoms
 Systemic symptoms: occur due to distant effects of
the cancer that are not related to direct or metastatic
spread. Some of these effects can include
 weight loss (poor appetite and cachexia),
 fatigue,
 excessive sweating (especially night sweats),
 anemia (low red blood cell count) and other specific
conditions termed paraneoplastic phenomena.
 These may be mediated
by immunological or hormonal signals from the cancer
cells.
Differentiating Benign and Malignant
Neoplasms
Differentiating Benign and Malignant
Neoplasms
 Benign Malignant
Gross features
Smooth surface with fibrotic capsule; Irregular surface without encapsulation

compressed surrounding destruction of surrounding tissues.

tissues.

Small to large Small to large

es very large.

Slow rate of growth . Rapid rate of growth

Rarely fatal
(except in central nervous system) Usually fatal if untreated.

even if untreated
Microscopic features
Growth by compression of Growth by invasion of surrounding
surrounding tissue. tissue

Highly differentiated, Well or poorly differentiated.

resembling normal tissue
of origin microscopically. Increased miotic activity; abnormal

Cells similar to normal and Cytologic abnormalities

resembling one another,
presenting a uniform appearance.

Few mitotic figures;

Well–formed blood vessels. Blood vessels numerous and poorly formed
Necrosis unusual; Necrosis and hemorrhage common.
other degenerative changes may be present.

Distant spread (metastasis) does not occur. Metastasis to distant sites

Mechanisms & Causes of Neoplasia
 Neoplasia is an abnormality of cell growth and
multiplication characterized by the following
features:
 (1) excessive cellular proliferation that typically
but not invariably produces an abnormal mass, or
tumor;
 (2) uncoordinated growth occurring without any
apparent purpose;
 (3) persistence of excessive cell proliferation
and growth even after the inciting stimulus that
evoked the change has been removed—ie,
neoplasia is an irreversible process.
 Alterations in cell growth can be physiologic (normal
responses to stimuli) or pathologic.
 These alterations of cell growth are potentially reversible
and include:
 Hypertrophy: an increase in cell size. Increase in skeletal
muscle fiber size is a physiologic response to exercise, but
the cardiac hypertrophy shown above is a pathologic
response to abnormally elevated blood pressure.
 Hyperplasia: an increase in the number of cells.
Postpartum breast lobules undergo hyperplasia for
lactation, but endometrial hyperplasia in a
postmenopausal woman is abnormal.

Tissue evidence of carcinogenic factors at
work
 Metaplasia: an initial change from normal cells to a
different cell type (he exchange of normal epithelium for
another type of epithelium. Metaplasia is reversible when
the stimulus for it is taken away ).

 Dysplasia: an increasing degree of disordered growth or

maturation of the tissue. Dysplasia is still a reversible
process. However, once the transformation to neoplasia has
been made, the process is not reversible.
 These terms are related since they represent the three steps
of the progression toward cancer:
 Dysplasia is the earliest form of pre-cancerous lesion
recognizable in a biopsy by a pathologist. Dysplasia can
be low grade or high grade (see CIS below). The risk of
low-grade dysplasia transforming into cancer is low.
 Carcinoma in situ is synonymous with high-grade
dysplasia in most organs. The risk of transforming into
cancer is high.
 Invasive carcinoma, commonly called cancer, is the final
step in this sequence. It is a disease that, when left
untreated, will invade the host (hence its name) and may
be lethal.
 Carcinoma in situ

 Carcinoma in situ (CIS) is an early form

of carcinoma defined by the absence of
invasion of surrounding tissues.
 In other words, the neoplastic
cells proliferate in their normal habitat,
hence the name "in situ" (Latin for "in its
place").
Carcinoma in situ
The most severe cases of dysplasia are sometimes referred to as "carcinoma in
situ." In Latin, the term "in situ" means "in place," so carcinoma in situ refers to an
uncontrolled growth of cells that remains in the original location. However,
carcinoma in situ may develop into an invasive, metastatic malignancy and,
therefore, is usually removed surgically, if possible.
Carcinoma in situ
Monoclonal Origin

 According to the concept of monoclonal origin, the

initial neoplastic change affects a single cell, which
then multiplies and gives rise to the neoplasm.
Field Origin

 A carcinogenic agent acting on a large number of

similar cells may produce a field of potentially
neoplastic cells.
 Neoplasms may then arise from one or more cells
within this field. In many cases the result is several
discrete neoplasms, each of which derives from a
separate clonal precursor.
The Lag Period

 A constant feature of all known agents that cause

neoplasms is the interval (lag period) between
exposure and development of the neoplasm.
Multiple Hits & Multiple Factors
 Carcinogenesis requires two hits.
 The first event is initiation (Figure 18-2), and the
carcinogen causing it is the initiator.
 The second event, which induces neoplastic
growth, is promotion, and the agent is the
promoter.
 The period between the first hit and the
development of clinically apparent cancer is the
lag period.
Oncogenes & Tumor Suppressor Genes
 There are two main categories of genes that regulate cell
growth, and the abnormal action of either or both may lead
to neoplasia.
 Proto-oncogenes (cellular oncogenes: c-onc) code for a
variety of growth factors, receptors, and signal-relay or
transcription factors
 tumor suppressor genes, which serve to down-regulate
the cell cycle. A net increase in the production of
stimulatory (promoter) factors, a decrease in inhibitory
(suppressor) growth factors, or the production of
functionally abnormal factors may lead to uncontrolled cell
growth.
Mechanisms of Gene Activation &
Inactivation
 Activation and inactivation may occur through
several mechanisms
 (1) mutation, including single nucleotide loss
(frameshift) or substitution (nonsense or missense
codon), codon loss, gene deletion or more major
chromosomal loss;
 (2) translocation to a different part of the
genome where regulatory influences may favor
inappropriate expression or repression;
 (3) insertion of an oncogenic virus at an adjacent
site
Activation and inactivation may occur through several
mechanisms

 (4) amplification (production of multiple copies of

the proto-oncogenes), which appear as additional
chromosome bands or extra DNA fragments (double
minutes);
 (5) introduction of viral oncogenes
 (6) derepression (loss of suppressor control).
 Gene activation: accelerated cell proliferation
 Loss of tumor suppression: loss of the brakes on cell
growth
 Persistence: accumulation of cells from lack of
apoptosis
 Replication: acquisition of the ability to keep dividing
Oncogenic Agents; Carcinogens
 Radiation Oncogenesis
 Solar ultraviolet radiation is associated with different
kinds of skin cancer
 X-Ray Radiation
 As x-rays capable of greater penetration were
developed, the second generation of radiologists
suffered an increased incidence of leukemia.
 Radioisotopes
 The carcinogenic effect of radioactive materials
was first recognized when many cases of
osteosarcoma occurred among factory workers
who used radium-containing paints to produce
luminous watch faces.
 Radioactive radium is metabolized in the body in
much the same way as calcium and is therefore
deposited in bone, where it induces osteosarcoma
Viral Oncogenesis
 Both DNA viruses and RNA viruses can cause
neoplasia
 DNA viruses insert their nucleic acid directly into
the genome of the host cell. Normally, virus
replication ensues. In the oncogenic DNA viruses,
replication is sporadic or absent.
 RNA viruses require RNA-directed DNA
polymerase (reverse transcriptase), an enzyme that
causes production of a DNA copy of the RNA viral
genome; this DNA copy (provirus) can then be
inserted in the host genome.
Local Effects of Tumor.
Mass-presentation as tissue lump or tumor
Ulcer -destruction of epithelial surfaces (eg, stomach, colon,
mouth, bronchus)
Hemorrhage-from ulcerated area or eroded vessel
Pain-Any site with sensory nerve endings; tumors in brain
and many viscera are initially painless
Seizures-tumor mass in brain; seizure pattern often localizes
the tumor
Cerebral dysfunction-wide variety of deficits depending on
site of tumor
Obstruction-of hollow viscera by tumor in the wall; bronchial
obstruction leads to pneumonia
Local Effects of Tumor.
Localized loss of sensory or motor
function-compression or destruction of
nerve or nerve trunk; classic example is
involvement of recurrent laryngeal nerve
by lung or thyroid cancer, with resulting
hoarseness
Edema-due to venous or lymphatic
obstruction
Local Effects of Tumor.
Perforation-of ulcer in viscera; in bowel may
produce peritonitis
Bone destruction-pathologic fracture, collapse
of bone
Inflammation-of serosal surface, pleural
effusion, pericardial effusion, ascites
Space–occupying lesion-raised intracranial
pressure in brain neoplasms; anemia due to
displacement of hematopoietic cells by
metastases to the bone marrow
HOST DEFENSE AGAINST TUMORS: TUMOR
IMMUNITY
 Antitumor Effector Mechanisms
 NK cells are lymphocytes that are capable of
destroying tumor cells without prior sensitization;
they may provide the first line of defense against
tumor cells
 Cytotoxic T Lymphocytes -in humans, they seem
to play a protective role, chiefly against virus-
associated neoplasms ( CD8+ cells that can kill
autologous tumor cells)
 Macrophages -activated macrophages exhibit
cytotoxicity against tumor cells in vitro.
 T cells, NK cells, and macrophages may collaborate in
antitumor reactivity
 Humoral Mechanisms
 Although there is no evidence for the protective effects
of anti-tumor antibodies against spontaneous tumors,
administration of monoclonal antibodies against
tumor cells can be therapeutically effective
Effects of Neoplasia on the Host
 Direct Effects of Local Growth of Primary Tumors
 The signs and symptoms arising from local growth of a
benign neoplasm or a primary malignant neoplasm vary
with:
 the site of the lesion,
 the nature of the surrounding anatomic structures,
 and the overall rate of growth of the neoplasm.
 The growing tumor may compress or destroy adjacent
structures, cause inflammation, pain, vascular changes,
and varying degrees of functional deficits
 Metastatic deposits form growing tumors that may
compress and destroy adjacent tissues in the same way that
a primary lesion does
Paraneoplastic (Nonmetastatic) Syndromes
 Cancer may also cause various signs and symptoms distant
from the primary lesion that are unassociated with
metastases; these effects are termed paraneoplastic (or
nonmetastatic) syndromes.
 They are:
 production of biologically active substances by the tumor
cells, such as hormones.
 formation of soluble immune complexes
 secretion of substances not yet characterized.
 The most common syndromes are hypercalcemia,
Staging

 The most common systems for staging employs the

TNM classification .
 " T" score is based upon the size and/or extent of
invasion.
 The " N" score indicates the extent of lymph node
involvement.
 The "M" score indicates whether distant metastases are
presen
Grading
 Grading schema are based upon the microscopic
appearance of a malignant neoplasm with H&E
staining. (Benign neoplasms are, by definition, always
well differentiated.)
In the diagram below utilizing an
adenocarcinoma as an example
Grading of Malignant Neoplasms

Grade Definition

I Well differentiated

II Moderately
differentiated
III Poorly differentiated

IV Nearly anaplastic
Early Diagnosis
 Cytologic Diagnosis
 Exfoliated cells can be identified in samples of sputum,
urine, cerebrospinal fluid, and body fluids. Recognition of
malignant cells in blood (as in the leukemias) or bone
marrow smears (leukemias, myeloma, metastatic
carcinoma) is based upon similar cytologic principles
 Brushing or scraping of epithelium or of a lesion that has
been visualized by endoscopy (bronchoscopy, gastroscopy,
colposcopy) may be performed to obtain cells for
examination.
 A fine (22-gauge) needle can be passed into virtually any
location to aspirate material directly from a mass lesion
(fine-needle aspiration (FNA)).
Early Diagnosis
 Histologic Diagnosis
 The diagnosis may be based on examination of the
entire neoplasm removed at surgery (excisional
biopsy)
 or examination of a sample of the neoplasm obtained
either by incisional biopsy or with a large-bore cutting
needle
Radiologic Diagnosis
 computer tomography (CT)
and magnetic resonance imaging (MRI) scans, are
invaluable for localizing masses as part of the primary
diagnosis or for staging tumors
Tumor Markers
Biochemical assays for tumor-associated enzymes,
hormones, and other tumor markers in the blood
cannot be utilized for definitive diagnosis of cancer
Genetic Testing
 Genetic markers include chromosomal alterations
(translocations, deletions, duplication, etc.); specific
gene defects; single nucleotide polymorphisms, and
gene rearrangements. Detection of specific genes
(such as BRCA-1 for breast cancer) may suggest an
increased risk for some malignancies.
Autopsy
 Sometimes neoplasms are not detected or completely
diagnosed during life. The autopsy serves as a means
of quality assurance for clinical diagnostic methods, as
a way of confirming diagnoses helpful in establishing
risks for family members
Treatment of Neoplasms
 Surgery:
 Malignant Neoplasms
 Wide Local Excision
 Surgical treatment of malignant neoplasms is more
difficult because they tend to infiltrate tissues. Local
excision requires careful pathologic examination
(including frozen sections as required) of the margins
of resection to ensure complete removal
 Lymph Node Removal
 Malignant neoplasms with a high risk of early
lymphatic metastasis are often treated by removal not
only of the affected tissue but also of the lymph node
group of primary drainage (radical surgery);
 Palliative Surgery
 Surgery also plays an important role in palliation
of symptoms by relieving pain and restoring
function in patients with incurable cancer.
 For example, surgical decompression of the spinal
cord is performed when vertebral metastases
threaten to cause paraplegia, and surgery may be
used to bypass an obstructed esophagus and
permit swallowing.
 Radiation Therapy-the more rapidly growing the
neoplasm, the more likely it is to be radiosensitive;
 The effect of radiation in a given neoplasm can be
predicted on the basis of past experience with
radiation therapy in similar neoplasms
 Chemotherapy
 Anticancer drugs act in one of several ways:
 (1) by interfering with cell metabolism and
ribonucleic acid (RNA) or protein synthesis
(antimetabolites);
 (2) by blocking deoxyribonucleic acid (DNA)
replication and mitotic division (antimitotic
agents);
 or (3) by exerting hormonal effects
 Immunotherapy
 Attempts to stimulate the immune system
(Interferon and interleukin-2, monoclonal antibodies )
 One promising approach uses the antibody to carry
cytotoxic drugs, toxins, or radioisotopes to the tumor
site.